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1、乙肝抗病毒治疗进展 北京佑安医院 陈新月 教授慢性乙肝需要长期治疗，治疗目标是长期抑 制病毒复制，阻止疾病进展l首要目标：清除或永久性抑制乙肝病毒l近期临床治疗目的 终止或减少肝脏的坏死炎症。减轻肝脏的 炎症，预防肝脏纤维化和/或肝脏失代偿的 发生，能持续保持HBV DNA阴性和ALT 的正常l远期临床治疗目的 避免ALT的活动及导致的肝脏失代偿，以 及预防肝硬化和/或肝细胞肝癌(HCC)的发 生，最终延长生存期。 参考文献：慢性乙肝处理亚太共识：更新Journal of Gastroenterology and Hepatology (2003) 18,239245 慢性乙型肝炎治疗的展望1
2、. 核苷类似物 - 拉米夫定 - 阿德福韦 - L-nucleosides (LdT, LdC) - 恩替卡韦 - Emtricitabine (FTC) - Clevudine (L-FMAU) - LY582563 (Eli Lilly) 2. 病毒包装抑制剂 - AT-61; AT 130 (作用于RNA包裹过 程 ) - Bay 41- 4109 (加速核心蛋白降解) 3. 基因治疗 -小分子干扰RNA(siRNA) - 反义寡核苷酸1.干扰素-alpha - 常规干扰素- 复合干扰素- 聚乙二醇干扰素A. 直接抗病毒药物B. 抗病毒/免疫调节剂C.免疫调节剂 1. 非特异性免疫治疗
3、- 白介素-12、 白介素-18 - 胸腺肽-alpha2. HBV特异性免疫治疗 - 抗HBsAg抗体 - HBV蛋白疫苗 (表面抗原、核心抗原) - HBV DNA 疫苗 - T细胞体外扩增 - 树突状细胞免疫治疗NNNNOPOON H2OOOOOl单磷酸腺苷的核苷酸类似物lHBV DNA链合成的终止物l有效抑制HBV野生株和拉米夫定耐药株l10mg，一天一次l48周安全性与安慰剂相似l持续抑制HBV DNA，耐药发生的阈值高阿德福韦酯阿德福韦酯阿德福韦治疗HBeAg (-)慢性乙肝96周对病毒 学，生化学及组织学的改善研究设计* Patients in ADV 10 mg group r
4、e-randomized in a 2:1 fashion at week 48 * All patients who received ADV 10 mg in second 48 week period0Week 48 Week 96RandomizedADV 10 mg*Placebo (n = 62)ADV 10 mg (n = 60)Placebo (n = 62)ADV 10 mg (n = 80)Placebo (n = 40)PlaceboLiver BiopsyLiver BiopsyLiver Biopsy (optional)ADV 10 mg (n = 125)3 ad
5、ditional years*97% completed92% completedADV 10 mg*LLQ = 1000 copies/mL平均血清 HBV DNAPLB - ADV ADV - ADV ADV - PLB3456780 12 24 36 48 60 72 84 96WeeksLog 10 copies/mLLLQ*2 48040608010012001224364860728496WeeksALT (IU/L)PLB - ADV ADV - ADV ADV - PLB平均血清 ALT (IU/L) 1ULN for males = 43 IU/L, females = 34
6、 IU/LULN14 8保持ALT 正常的病人比例01020304050607080901000 4 8 1224364860728496Patients (%)Weeks80% 76%32%PLB - ADV ADV - ADV ADV - PLB1ULN for males = 43 IU/L, females = 34 IU/L病人96周时肝活检 Knodell评分从基线变化情况PLBn = 20n = 19ADVn = 9ADV-5-4-3-2-10+1+20%n = 20ADVn = 19ADVn = 9 PLBPLB - ADV ADV - ADV ADV - PLB 489696
7、964848Weeks恶化改善Median ChangePLB - ADV ADV - ADV ADV - PLB 489696964848Weeks402002040608035%74%38% 30%63%50%改善恶化n = 19n = 19n = 20n = 20n = 8n = 8Patients (%)40%25%0%0%0%13%48 / 96周时肝纤维化评估情况 Intent to treat population of patients with biopsies at baseline, week 48 and week 96ALT 升高 10 x ULNALT 10 x U
8、LN 13% 5% 35%ALT 10 x ULN with:胆红素 2.5 mg/dL 或 5%a 0% 3%b 1 mg/dL 高于基线值白蛋白 3 g/dL 2%a 0% 0% PT 延长 1.5 秒 2%a 0% 0% above ULN a Events for the PLB to ADV group took place during year one on PLB b Events for the ADV to PLB group took place during year two while on PLBPLB - ADV n=60ADV - ADV n=79ADV - P
9、LB n=40耐药评估l0，48，96周时进行HBV DNA 聚合酶序列分析l发现rtN236T位点变异 48周发生率0% 96周时发生率2.5%1lrtN236T变异株对阿德福韦敏感性下降 但无论体内/体外试验均显示对lamivudine仍具敏感性1 Yang et al AASLD (2003) poster # 1141结论 l96周阿德福韦的治疗使HBV DNA与 ALT持续降低 组织学改善 l中断阿德福韦的治疗出现 HBV DNA 和 ALT抑制的丧失 组织学改善出现反复 l48周安全性与安慰剂相似 96周安全性与48周时相似l阿德福韦耐药现象出现的晚且发生率低lThree year
10、 of Adefovir demonstrates sustained efficacy in presumed precore mutant chronic CHB patients in a long term safety and efficacy studyEASL 2004ADV 10mgADV 10mg Item week 96 n=79Week 144 N=67 Median change: HBV DNA-3.47-3.63% HBV DNA Undetectable by PCR71%79%ALT Median Change(IU/L)-59-54ALT % normaliz
11、ed73%(47/64)69%(43/62)rtN236T/A181V mutations3.0%5.9%ResultStudy 435 研究目的l评价阿德福韦在肝移植前或后的病人中的疗效及 安全性l评价阿德福韦对于肝移植前已经出现拉米夫定耐 药病人的疗效 Schiff et al. Hepatology, in pressStudy 435 Study Designl开放，多中心，国际临床研究l需要进行肝移植的病人或肝移植后的病人（均 为拉米夫定治疗失败） HBV DNA 6 log10 copies/mL ALT 1.2 x ULNl在原有用药基础上加用ADV 10 mg /天 根据医生判
12、断继续使用拉米夫定和 HBIg Study 435 研究终点lHBV DNA较基线的变化l(%)病人无法检测出HBV DNA Roche Amplicor MonitorTM PCR (LLQ 400 copies/mL*)lALT的变化及 ALT正常的比例 lChild-Pugh-Turcotte (CPT) 评分变化*The LLQ was changed from 400 to 1,000 copies/mL during the course of the studyStudy 435 基线情况Study 435 HBV DNA的平均变化0 4 8 12 24 36 48 WeeksP
13、ost-OLT n = 169 161 156 149 116 88 57Pre-OLT n = 103 98 91 84 52 28 13Log10copies/mL0- 1- 2- 3- 4- 4.3 log10 copies/mL- 4.1 log10 copies/mL- 5Week 48 pre- and post-transplantation (p 0.001 as compared to baseline)Post-OLTPre-OLTStudy 435 48周时其他研究终点*Roche Amplicor MonitorTM PCR assay (LLQ 400 copies/
14、mL or 1,000 copies/mL) In patients with abnormal values at baseline24 week data移植前病人回顾性调查结果 Retrospective Survey of Patient Outcomes (Pre-OLT)Study 435 Survey Questionsl开始使用阿德福韦治疗后 病人接受肝移植了吗?l病人的病情是否得到改善从而允许 接受移植? 从等待移植的名单上去除?Pre-OLT patients n=100*Yes 43 (43%)No 57 (57%) 病人在接受阿德福韦治疗后接受肝移植了吗?*Survey
15、s returned for 102 of 128 pre-OLT patients; 2 NA病人使用阿德福韦后病情是否改善 并允许接受移植手术Received OLT n=43*Remained on ADV therapy 3 of 6 were either on ADV 4 weeks prior to OLT or began ADV after OLTYes* 37 (86%)No 6 (14%)阿德福韦改善病情是否可以使病人从等待移 植的名单上去除?没有接受 OLT n=57Removed from OLT wait-list*21 (37%)Remained on OLT wait-list*36
